Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis.

Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA.

Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases.

Keloid disorder, a group of fibroproliferative skin diseases, is characterized by unremitting accumulation of the extracellular matrix (ECM) of connective tissue, primarily collagen, to develop cutaneous tumors on the predilection sites of skin. There is a strong genetic predisposition for keloid formation, and individuals of African and Asian ancestry are particularly prone. The principal cell type responsible for ECM accumulation is the myofibroblast derived from quiescent resident skin fibroblasts either through trans-differentiation or from keloid progenitor stem cells with capacity for multi-lineage differentiation and self-renewal.

Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion formation.

Background: Intra-abdominal adhesions are a major cause of morbidity after abdominal or gynecologic surgery. However, knowledge about the pathogenic mechanism(s) is limited, and there are no effective treatments. Here, we investigated a mouse model of bowel adhesion formation and the effect(s) of an Federal Drug Administration-approved drug (trametinib) in preventing adhesion formation.

Therapeutic Approaches to Radiation-Induced Fibrosis.

Radiation induced fibrosis (RIF) is a common morbidity in patients being treated for cancer with radiation. Off-target effects result in intense inflammatory responses which ultimately results in the generation of extracellular matrix (ECM) producing myofibroblasts which mediate a progressive fibrosis resulting in scarring and organ and tissue dysfunction. Unfortunately, currently, there are no effective therapies to block the excess accumulation of ECM.

Human Fibrotic Diseases: Current Challenges in Fibrosis Research.

Human fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals, the incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents. The fibrotic disorders encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis.

Keloids: The paradigm of skin fibrosis - Pathomechanisms and treatment.

Keloids, fibroproliferative dermal tumors with effusive accumulation of extracellular matrix (ECM) components, particularly collagen, result from excessive expression of growth factors and cytokines. The etiology of keloids is unknown but they occur after dermal injury in genetically susceptible individuals, and they cause both physical and psychological distress for the affected individuals. Several treatment methods for keloids exist, including the combination therapy of surgical excision followed by intralesional steroid therapy, however, they have high recurrence rate regardless of the current treatment method.

Pathobiological mechanisms of peritoneal adhesions: The mesenchymal transition of rat peritoneal mesothelial cells induced by TGF-β1 and IL-6 requires activation of Erk1/2 and Smad2 linker region phosphorylation.

Peritoneal adhesions, primarily caused by surgical procedures, are the leading cause of pelvic pain, bowel obstruction, and infertility. TGF-β1 and IL-6 have been found to be elevated in the peritoneal fluid of patients during/after abdominal surgery. However, it remains to be determined whether these cytokines interact and facilitate adhesion formation by promoting mesothelial to mesenchymal transition (MMT).

New frontiers in fibrotic disease therapies: The focus of the Joan and Joel Rosenbloom Center for Fibrotic Diseases at Thomas Jefferson University.

Fibrotic diseases constitute a world-wide major health problem, but research support remains inadequate in comparison to the need. Although considerable understanding of the pathogenesis of fibrotic reactions has been attained, no completely effective therapies exist. Although fibrotic disorders are diverse, it is universally appreciated that a particular cell type with unique characteristics, the myofibroblast, is responsible for replacement of functioning tissue with non-functional scar tissue.

Absence of γ-sarcoglycan alters the response of p70S6 kinase to mechanical perturbation in murine skeletal muscle.

Background: The dystrophin glycoprotein complex (DGC) is located at the sarcolemma of muscle fibers, providing structural integrity. Mutations in and loss of DGC proteins cause a spectrum of muscular dystrophies. When only the sarcoglycan subcomplex is absent, muscles display severe myofiber degeneration, but little susceptibility to contractile damage, suggesting that disease occurs not by structural deficits but through aberrant signaling, namely, loss of normal mechanotransduction signaling through the sarcoglycan complex.

Mechanosensitive release of adenosine 5'-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: a mechanism for purinergic involvement in chronic strain.

As adenosine 5'-triphosphate (ATP) released from astrocytes can modulate many neural signaling systems, the triggers and pathways for this ATP release are important. Here, the ability of mechanical strain to trigger ATP release through pannexin channels and the effects of sustained strain on pannexin expression were examined in rat optic nerve head astrocytes. Astrocytes released ATP when subjected to 5% of equibiaxial strain or to hypotonic swelling.

Recombinant insulin-like growth factor-1 activates satellite cells in the mouse urethral rhabdosphincter.

Background: The goal of this study is to demonstrate the efficacy of a new method for the treatment of urinary incontinence by stimulation of urethral rhabdosphincter satellite cells. We show that satellite cells do exist in the sphincter muscle of retired male mice breeders by staining for c-Met, a satellite cell specific protein. Once activated by recombinant mouse Insulin-like Growth Factor-1(rIgf-1), the satellite cells develop into muscle cells within the rhabdosphincter thereby potentially strengthening it.

Urinary diversion results in marked decreases in proliferation and apoptosis in fetal bladder.

Purpose: We sought to determine if bladder cycling is required for remodeling during fetal development.

Materials And Methods: For this study 5 fetal sheep bladders were harvested after 2 weeks of urinary diversion, initiated at approximately 90 days of gestation. Six unoperated sheep bladders of approximately 105 days of gestational age were used as controls.

Neurons respond directly to mechanical deformation with pannexin-mediated ATP release and autostimulation of P2X7 receptors.

Mechanical deformation produces complex effects on neuronal systems, some of which can lead to dysfunction and neuronal death. While astrocytes are known to respond to mechanical forces, it is not clear whether neurons can also respond directly. We examined mechanosensitive ATP release and the physiological response to this release in isolated retinal ganglion cells.

Beta and gamma-sarcoglycans are decreased in the detrusor smooth muscle cells of the partially obstructed rabbit bladder.

Purpose: We evaluated and quantified the levels of sarcoglycans present in the detrusor muscle layer of rabbits with partial bladder outlet obstruction.

Materials And Methods: Rabbits underwent surgery, as previously described, to partially obstruct the urethra. One, 3, 7 and 14 days after obstruction the detrusor muscle layer was dissected free of the remaining bladder tissue and extracted with detergent to isolate the transmembrane components of the dystroglycan-glycoprotein complex.

Effect of fibroblast growth factor-1 on the expression of early growth response-1 in human periodontal ligament cells.

Background And Objectives: Early growth response-1 is a nuclear transcription factor implicated in regulating cell proliferation. Fibroblast growth factor-1 is the prototypic fibroblast growth factor involved in the proliferation and differentiation of various cell types. Expression of early growth response-1 induced by fibroblast growth factor-1 thus may be very important for cell growth, during both development and wound healing in oral tissue.

Altered extracellular matrix expression in the diverted fetal sheep bladder.

Purpose: It is unclear whether filling and emptying are important to bladder development. We tested this in an experimental preparation.

Material And Methods: Urinary diversion was performed in 7 fetal lambs at 90 days of gestation and 6 unoperated fetal lambs served as controls.

Smooth muscle trans-membrane sarcoglycan complex in partial bladder outlet obstruction.

The urinary bladder experiences both distension and contraction as a part of the normal filling and emptying cycle. To empty properly, tension generated intracellularly in a smooth muscle cell must be smoothly and efficiently transferred across its sarcolemma to the basement membrane, which mediates its binding to both the extracellular matrix and to other cells. As a consequence of urethral obstruction, the bladder cannot generate appropriate force to contract the organ, thereby leading to inefficient emptying and associated sequelae.

Compression and tension: differential effects on matrix accumulation by periodontal ligament fibroblasts in vitro.

Human periodontal ligament fibroblasts were subjected to 10% cyclic equibiaxial tensional and compressive forces in vitro. Media supernatants were analyzed for changes in total protein, extracellular matrix proteins type I collagen and fibronectin, as well as MMP expression by gelatin zymography and Western blot. RNA analyses for changes in collagen, MMP-2, and TIMP-2 were carried out by either Real-time PCR and/or Northern blot.

Matrix synthesis by bladder smooth muscle cells is modulated by stretch frequency.

The bladder is a physically active organ that undergoes periodic stretching as a part of its normal function. To determine the role that stretching or mechanical deformation may play in altering the synthetic phenotype of bladder wall cells, a series of experiments were carried out to quantify several extracellular matrix (ECM) messenger ribonucleic acids (mRNAs) and their corresponding protein levels after mechanical challenge. Bladder smooth muscle cells were grown on distensible membranes in an apparatus that can reliably and reproducibly subject cells to well-characterized periods of mechanical stretching.

Regulation of Cyr61/CCN1 gene expression through RhoA GTPase and p38MAPK signaling pathways.

Cysteine-rich protein 61 (Cyr61/CCN1) is an angiogenic factor and a member of a family of growth factor-inducible immediate-early genes with functions in cell adhesion, proliferation and differentiation. We investigated the regulatory mechanisms and signaling pathways involved in Cyr61/CCN1gene activation in smooth muscle cells. Treatment of these cells with sphingosine 1-phosphate (S1P), a bioactive lysolipid, increased rapidly but transiently the expression of the Cyr61/CCN1 gene at both the mRNA and protein levels.

Partial bladder outlet obstruction alters Ca2+ sensitivity of force, but not of MLC phosphorylation, in bladder smooth muscle.

Partial bladder outlet obstruction in the rabbit produces changes in bladder function similar to those seen clinically in patients with obstructive uropathies. Whole organ function is significantly altered, as are the smooth muscle cells inside the bladder wall. This study was designed to determine whether outlet obstruction alters smooth muscle function at the level of contractile filaments.

Correlation of P-cadherin and beta-catenin expression and phosphorylation with carcinogenesis in rat tongue cancer induced with 4-nitroquinoline 1-oxide.

Using biochemical and immunohistochemical techniques, we have investigated P-cadherin, beta-catenin, c-src and c-met protein expression, and phosphorylation of beta-catenin in a rat model of tongue cancer induced with 4-nitroquinoline 1-oxide. Six-week-old male Sprague-Dawley rats were given either normal drinking water (controls) or 50 ppm 4NQO solution as drinking water for 16 and 20 weeks. This treatment produced dysplasia and well-differentiated squamous cell cancer in rat tongues after 16 and 20 weeks, respectively.

Response of the fetal sheep bladder to urinary diversion.

Purpose: In adults urinary diversion results in bladder atrophy and a rapid decrease in contractile function. Little is known about the effects of urinary diversion on bladder development. In this regard we characterized the responses of fetal sheep bladder strips obtained from animals that underwent urinary diversion.